Protecting Human Subjects: What everyone needs to know

1
Protecting Human SubjectsWhat everyone needs to
know

• Office for Human Research Studies (OHRS)
• December 2009
• [phone] ? ohrs_at_dfci.harvard.edu

2
OHRS

• Michele Russell-Einhorn, JD
• Senior Director, Office for Human Research
  Studies
• Amanda Hammond, JD
• Deputy Director, Office for Human Research Studies

3
Goals of Training

• Briefly review scientific review process
• Review regulatory issues involved in the
  protection of human subjects in research to
  ensure adequate substantive review, consistency
  and thoroughness of IRB review and approval and
  continuing oversight of research involving human
  subjects.

4
General Overview

• The DF/HCC scientific review committees and the
  DFCI IRBs review all adult and pediatric
  cancer-related research on behalf of BIDMC BWH
  CHB DFCI and MGH.

5
National Cancer Center Grant

• DF/HCC Scientific Review Committees-four
  committees and an ongoing expedited review
  process that fall under the protocol review and
  monitoring system process for oncology research
  set out in the NCI Cancer Center Support Grant.
• The Cancer Center Grant requires that we keep the
  scientific review and IRB review functions
  separate and distinct.

6
National Cancer Institute

• Cancer Center Support Guidelines require
• 1. Scientific review for merit and progress and
  accrual
• 2. No guidelines for determining which post
  approval events such as amendments deviations
  violations or adverse events require re-review
  by a scientific review committee.

7
Scientific Review vs. IRB Review

• There are differences between scientific review
  and IRB review, e.g.,
• -conditional approvals
• -annual progress review

8
Institutional Review Boards

• DFCI IRBs operate under a Federal Wide Assurance
  that we have with the U.S. Department of Health
  and Human Services.
• DFCI IRBs operate under Federal regulations that
  specifically dictate the operations and
  substantive review of the IRBs.
• DFCI IRBs, on behalf of the DF/HCC, currently
  have oversight of over 1750 open research
  protocols involving human subjects.

9
DFCI IRBs

• Information Relating to the Operation of IRBs

10
DFCI IRBs

• IRBs A and B
• meet on an alternating basis every Tuesday from
  12-2 pm.
• expertise to review any matter, but focus on new
  protocols and amendments.

11
DFCI IRBs

• IRBs C and F
• meet on an alternating basis every Thursday
  morning from 8-10 am.
• expertise to review any matter but focus on
  continuing reviews amendments adverse events
  and other events.

12
DFCI IRBs

• IRB D
• meets twice monthly on Mondays from 10-12 pm
• was known as the social and behavioral IRB or
  the minimal risk IRB, in fact
• reviews any research that is not technically
  clinical intervention research as well as
  research that is greater than minimal risk.
• additional bone marrow aspirates
• additional blood draws
• tissue repository research etc.

13
DFCI IRBs

• IRB E
• rapid response IRB
• small number of members and can respond quickly
  to an emergent situation.

14
DFCI IRBs

• IRB G
• Pediatric Panel
• Meets 1st and 3rd Monday of each month
• Expertise to review any pediatric matter

15
Institutions in the News
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JHU-FDA Warning Letter to PIMarch 31, 2003

• Our records indicate that you are aware of your
  sponsor obligationswe note that on September 15,
  1997, you submitted an IND application to the
  FDA(FDA) notified you in writing on October 24,
  1997, that you were prohibited from initiating
  any of the submitted protocols due to significant
  safety concerns and other protocol deficiencies
  including inadequate chemistry, purity, and
  pre-clinical data inadequate and confusing study
  procedures and protocols, lack of inclusion
  criteria, discontinuation criteria, and defined
  safety parameters and lack of methodology for
  adverse event monitoring, treatment, and
  follow-up of subjects.

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Carle Foundation Hospital
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University of Pittsburgh
21
Government Shutdowns

• Massachusetts Eye and Ear Infirmary
• UCLA
• VA Health Sys. Greater Los Angeles
• Rush Presbyterian St Lukes Med Ctr.
• University of Illinois Chicago
• Duke University Med Ctr.
• Univ. Texas Medical Branch Galveston
• University of Oklahoma Tulsa
• Johns Hopkins University

22
Still happens Weill Medical College, May 2004

• OHRP Findings
• OHRPs review of IRB documents reveals
  evidence that the IRB does not always make the
  required findings when reviewing research
  involving children, and when the findings are
  made, they are sometimes inappropriate (e.g. for
  protocol 0204-165, which involved a
  dose-finding, safety study of a drug in pediatric
  hypertensive patients, the IRB found that the
  protocol was approvable under HHS regulations at
  45CFR 46.404). Based on OHRPs discussions with
  the IRB chairperson and IRB members, OHRP is
  concerned that the IRB lacks a detailed
  understanding of HHS regulations at 45 CFR part
  46, subpart D, which require specific IRB
  determinations related to the risks and potential
  benefits when children are involved as subjects
  of research.

23
Weill Medical College, May 2004

• OHRP Findings
• (a) For protocol 0296-223, subjects were
  enrolled outside the protocol age range
• prior to IRB review and approval of the amended
  protocol.
• (b) Protocol 0800-354 stated that subjects would
  be randomized between
• metformin and placebo. During our interview, the
  investigator stated that, among
• other things, the protocol was changed to a
  single arm study without prior IRB
• review and approval.
• (c) For protocol 0801-842, between August 12,
  2002 and July 22, 2003, the
• protocol was changed from a double-blind study to
  a single blind study. OHRP
• could find no evidence of IRB review and approval
  of this protocol modification.
• Further, the continuing review form reviewed by
  the IRB on July 22, 2003 stated
• no changes since last continuing review.

24
Weill Medical College, May 2004

• OHRP Action
• In view of the above determinations and in order
  to ensure adequate protections for human
  subjects, OHRP hereby restricts the WMC assurance
  (FWA 93), pending satisfactory completion of the
  required corrective actions described below.

25
Emory

• Emory halts enrollment in cancer clinical trials
• Action at Winship Cancer Institute follows
  critical audit of procedures
• By Craig Schneider
• The Atlanta Journal-Constitution
• Tuesday, June 16, 2009
• Emory Universitys Winship Cancer Institute has
  stopped accepting new patients into clinical
  trials after a critical audit, even as it seeks
  to enhance its standing in the fight against
  cancer.
• The center voluntarily halted accepting new
  patients May 15 following a critical audit of
  record-keeping for research purposes. The audit
  was performed by the Eastern Cooperative Oncology
  Group, a cancer research group that works with
  Winship.
• The audit found deficiencies in the research
  files regarding patients, including missing test
  results and CAT scans, unreported vital signs
  such as blood pressure and heart rate, and
  unreported logs on how often a patient took his
  or her drugs.

26
Historical Overview

• The development of protections for human subjects
  in research.

27
Historical OverviewInternational

• Nazi Doctor Trials
• Nuremberg Code 1947
• Informed Consent
• Declaration of Helsinki
• World Medical Association, Ethical Principles for
  Medical Research Involving Human Subjects
• 1964 (revised 2000)

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Historical Overview

• Public Health Service (PHS) Policy
• Prior Review of Research by Institutional
  Associates (PPO 129, February 8, 1966)
• United States Public Health Service
• Syphilis Study at Tuskegee (1932 -1972)

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Historical OverviewUnited States -- 1974

• Congressional Hearings
• Senator Walter Mondale
• Senator Edward Kennedy
• HHS Regulations
• National Research Act
• National Commission for the Protection of
• Human Subjects of Biomedical and Behavioral
  Research, July 12, 1974

30
Historical OverviewThe Belmont Report April
18, 1979
31
Federal Oversight of Human Subject Research

• Federal Policy for the Protection of Human
  Subjects (Common Rule)
• Adopted 1991
• HHS Regulations
• Revised 1981, 1991
• FDA Regulations
• Revised 1981, 1991
• No Mandatory Protections if not covered by above

32
DHHS Federalwide Assurance (FWA)

• FWA requires compliance with 45 CFR 46 for
  Federally Funded/Supported Research
• All FDA regulated research must comply with
  applicable FDA regulations even in the absence of
  Federal Funding or Support

33
Federal Policy (Common Rule) for the Protection
of Human Subjects

• 18 Federal Agencies Adopted DHHS Subpart A
• Some Agencies Required Additional Protections
• VA requires compensation for research-related
  injuries
• DoD additional level of review (e.g., HSRRB) for
  certain types of research
• Some Agencies Never Adopted the Federal Policy
• Department of Labor Miners and Coal Dust
• Appalachian Regional Commission Telemedicine

34
DHHS Regulations45 CFR Part 46

• Subpart A ? Core Protections ? Common Rule
• IRB Review
• Informed Consent
• Subpart B ? Additional Protections
• Pregnant Women, Fetuses, and Neonates
• Subpart C ? Additional Protections
• Prisoners
• Subpart D ? Additional Protections
• Children

35
Subpart A Core Human Subject ProtectionsFederal
Policy (Common Rule), DHHS, FDA

• IRB Review (DHHS 45 CFR Part 46 and FDA 21 CFR
  Part 56)
• Initial Review
• Prospective Review of All Changes
• Reporting/Review of Unanticipated Problems
• Reporting/Review of Adverse Events
• Continuing Review at Least Annually
• Informed Consent (DHHS 45 CFR Part 46 and FDA 21
  CFR Part 50)
• Eight Required Elements
• Written Documentation
• Language Understandable to Subjects
• No Coercion or Undue Influence
• No Waiver of Subjects Rights

36
Roles and ResponsibilitiesInstitutional
Responsibility

• Institutional Commitment and Infrastructure
• Authorized Institutional Official
• IRB Chair, IRB Members, IRB Staff
• Data Safety Monitoring Committees/Boards (DSMBs)
• Other Institutional Committees (Audit)
• Research Investigators and Co-Investigators
• Everyone Else Involved in the Research Enterprise
  (sponsors)

37
Roles and ResponsibilitiesInstitutional Review
Board (IRB)

• Review and Approve Proposed Research
• Risks Minimized through Sound Research Design
• Risks Reasonable Relative to Benefits
• Subject Selection Equitable
• Informed Consent Obtained
• Informed Consent Documented
• Privacy and Confidentiality Protections Adequate
• Safety Monitoring is Adequate
• Protections for Vulnerable Subjects are Adequate
• Exercise Continuing Oversight of Research

38
Roles and ResponsibilitiesInstitutional Review
Board (IRB)

• IRBs are also required to review HHS grants to
  ensure that the protocol submitted to the IRB is
  consistent with the grant application

39
Risks Minimized Through Sound Research Design

• Family of Subject who died in Gene Therapy Trial
  sponsored by Targeted Genetics is suing the
  company, the IRB and the principal investigator.
• The basis of the lawsuit is not so much
  objections to the informed consent document as
  the contention that someone with a mild case of
  rheumatoid arthritis should not be enrolled in a
  gene therapy trial.
• The science of the protocol could not justify
  enrollment of this type of subject in the
  research.

40
Roles and ResponsibilitiesPrincipal
Investigators

• Accept responsibility for all aspects of the
  research
• Ensure adequate training for entire research team
• Ensure adequate supervision of entire research
  team
• Know and ensure compliance with
• All regulatory requirements
• All IRB requirements
• All protocol requirements
• Ensure adherence to enrollment criteria
• Monitor and report unanticipated problems and
  adverse events to sponsor and IRB

41
Roles and ResponsibilitiesPrincipal
Investigators

• University of Pittsburgh, FDA warning letter,
  September 15, 2009-John M Kirkwood
• 1. failed to conduct procedures required by
  protocol
• 2. changed protocol without going through the IRB
  and FDA
• 3. failed to follow-up and collect adverse event
  information
• 4. failed to report serious adverse events
  experienced by three subjects
• 5. failed to prepare and maintain case histories
• 6. failed to monitor the progress of the clinical
  investigation

42
Applying the Regulations to Research Involving
Human Subjects
43
Definition of ResearchHHS, Federal Policy
(Common Rule)

• Research means
• A systematic investigation
• Designed to develop or contribute to
  
• Generalizable knowledge
• Includes
• Research development
• Testing
• Evaluation
• Pilot Studies

44
Definition of Research

• Research means
• A systematic investigation designed to develop or
  contribute to generalizable knowledge
• What does Systematic mean?
• Carried out according to a plan
• Permitting logical conclusions to be drawn
• What does Generalizable mean?
• Beyond the immediate situation
• Beyond the institution

45
Manhattan Eye, Ear and Throat Hospital Incident
46
Definition of Human Subject

• Human Subject means
• a living individual
• about whom an investigatorconducting research
  obtains
• data through intervention or interaction with the
  individual, or
• identifiable private information
• -- 45 CFR 46.102(f)

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VCU Twin Study
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Definition of Human Subject

• Private Information means
• Information about behavior in a context in which
  an individual can reasonably expect that no
  observation or recording is taking place
• Information, provided for specific purposes, that
  the individual can reasonably expect will not be
  made public (e.g., a medical record)
• -- 45 CFR 46.102(f)

49
IRB Requirements and Procedures
50
Institutional Review Board (IRB)Mission,
Duties, Authorities

• Mission ? To protect the rights and welfare of
  individuals participating in research involving
  human subjects
• Duties ? To approve, disapprove, modify, suspend
  research as necessary to ensure protections for
  human subjects in research
• Authority ? To exercise final authority within
  the institution for ensuring adequate protections
  for subjects. Officials of the institution may
  not approve research if it has not been approved
  by an IRB.
• Institutional Authority Beyond Regulations ?
  Delegated to IRB
• Ethical Issues on behalf of institution
• Sanctioning Investigators for noncompliance
• Use of tainted data

51
IRB Review and Approval

• Routine oversight mechanisms
• Initial Review
• Continuing Review
• Review of Adverse Events
• Review of Unanticipated Problems
• Special oversight mechanisms
• Data Safety Monitoring Boards (DSMBs)
• Consent Monitors
• Random Audits of Research
• Continuing Education

52
IRB Approval (Initial or Continuing) Includes
Findings That

• Risks are minimized through sound research design
• Risks are reasonable relative to anticipated
  benefits
• Selection of subjects is equitable
• Informed consent will be obtained
• Informed consent will be documented
• Privacy and Confidentiality provisions are
  adequate
• Data safety monitoring is adequate
• Appropriate safeguards are included for
  vulnerable subjects

53
IRB Oversight Includes...

• Continued ethical evaluation of the research
• Monitoring of the research
• Monitoring of the informed consent process
• Analysis (as received) of new information,
  adverse events, and unanticipated problems
  involving risks to subjects and others
• Formal Continuing Review at intervals appropriate
  to the degree of risk and no less than annually
  

54
Types of IRB Review

• Determination whether activity is Human Subject
  Research
• Verification of Exemption
• Expedited Review
• Convened (Full Board) Review
• NOTE Initial and Continuing Review require
  votes of the convened IRB, meeting all quorum
  requirements, unless specific conditions for use
  of expedited review are satisfied

55
Institutional Review Board (IRB)Composition

• Minimum of 5 members
• Diverse in gender and racial background
• Sufficiently qualified in experience and
  expertise
• (e.g., pediatric expertise required to review
  research involving children)
• One scientific member
• Non-scientific member
• One member not otherwise affiliated with the
  institution
• Expertise in vulnerable populations for regular
  review of such research

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Convened (Full Board) Review

• Majority of Total Membership Must Be Present
• Non-Scientist Member Must Be Present (not lay
  member)
• Approval Requires a Majority of Those Members
  Present
• Vote Must Be Documented
• Same Requirements for Initial and Continuing
  Review
• Important that documentation demonstrate that the
  IRB is making the appropriate regulatory
  determinations

57
IRB Meetings and Record Keeping

• All members receive complete set of materials
• Adequate time to review materials
• Minutes of meetings must be comprehensive
• Attendance and votes should be recorded
• OHRP permits teleconferencing if each
  participating member (i) has received all
  pertinent material prior to the meeting and (ii)
  can actively and equally participate in the
  discussion of all protocols

58
Types of IRB determinations

• Approval
• Conditional Approval
• Deferral
• Disapproval

59
Conditional ApprovalFrom OHRP Common Findings

• Contingent Approval of Research with Substantive
  Changes and no Additional Review by the Convened
  IRB.
• OHRP finds that the IRB frequently approves
  research contingent upon substantive
  modifications or clarifications without requiring
  additional review by the convened IRB.

60
Expedited ReviewMinor Changes to Approved
Research

• MINOR changes in previously approved research
• During the established approval period
• Conducted by Chair or IRB member designated by
  Chair
• Must be reported to full IRB
• No disapprovals, e.g., a decision to disapprove a
  requested deviation must be sent to the full
  board.
• -- 45 CFR 46.110

61
Expedited Review ListInitial or Continuing
Review

• Conducted by Chair or IRB member designated by
  Chair
• Only minimal risk research
• Must fit into a category on November 1998 list
• All other provisions and requirements apply
• Can only approve research -- Cannot disapprove
• Must be reported to full IRB
• -- 45 CFR 46.110 21 CFR 56.110

62
Expedited Review

• Minimal Risk Research in the Following
  Categories
• 1) Clinical studies of drugs and medical devices
  where an IND (drugs) or IDE (devices) is not
  required.
• 2) Collection of blood samples by finger stick,
  heel stick, ear stick, or venipuncture
• a) from healthy, non-pregnant adults weighing at
  least 100 lbs 550 ml in 8-wk period, limited to
  2 collections per week
• b) from other adults and children, not more than
  50 ml or 3 ml per kg in 8-wk period, limited to 2
  collections per week.

63
Expedited Review

• Minimal Risk Research in the Following
  Categories
• 3) Prospective collection of biological specimens
  by noninvasive means
• 4) Collection of data through noninvasive
  procedures (not involving general anesthesia or
  sedation) employed in clinical practice,
  excluding procedures involving x-rays or
  microwaves. Where medical devices are employed,
  they must be cleared/ approved for marketing.
  (Studies intended to evaluate the safety and
  effectiveness of the medical device are no
  generally eligible for expedited review,
  including studies of cleared medical devices for
  new indications.)

64
Expedited Review

• Minimal Risk Research in the Following
  Categories
• 5) Research involving materials (data, documents,
  records, or specimens) that
• have been collected
• will be collected for non-research purposes
• 6) Collection of data from voice, video, digital,
  or image recordings made for research purposes.

65
Expedited Review

• Minimal Risk Research in the Following
  Categories
• 7) Research on individual or group behavior or
  characteristics -- cognition, motivation,
  identity, language, communication, cultural
  beliefs/practices, social behavior survey,
  interview, oral history, focus group, program
  evaluation, human factor, quality assurance
  methodologies.

66
Expedited Review

• Minimal Risk Research in the Following
  Categories
• 8) Continuing review of research previously
  approved by the convened IRB where
• a) the research is permanently closed to new
  enrollments, all subjects have completed all
  research-related interventions, and research
  remains active only for long-term follow-up of
  subjects or
• b) no subjects have been enrolled and no
  additional risks have been identified or
• c) remaining research activities are limited to
  data analysis.

67
Expedited Review

• Minimal Risk Research in the Following
  Categories
• 9) Continuing review of research where the IRB
  has determined and documented at a convened
  meeting that the research involves no greater
  than minimal risk, and no additional risks have
  been identified.
• Critical Catchall Provision Note documentation
  requirement

68
Expedited ReviewCompliance Problems

• Inappropriate use of expedited review
• greater than minimal risk
• no appropriate category
• failure to document category and determination
• Greater than minor changes to approved research
• Inappropriate use for Continuing Review

69
Exempt Research
70
Six Exemptions45 CFR 46.101(b)

• 1) Research conducted in
• Established or commonly accepted educational
  settings
• Involving normal educational practices
• Instructional strategy comparisons

71
Six Exemptions45 CFR 46.101(b)

• 2) Research involving the use of
• Educational tests (cognitive, diagnostic,
  aptitude, achievement), survey procedures,
  interview procedures, or observation of public
  behavior
• UNLESS
• information is recorded in an (directly or
  indirectly) identifiable manner (NOTE Coded
  identifiable)
• AND
• disclosure would place subject at risk of
  criminal or civil liability or be damaging to
  financial standing, employability, or reputation

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Six Exemptions45 CFR 46.101(b)

• Special Consideration involving Children
• Survey and Interview Research Involving Children
  IS NOT Exempt
• Passive Observation of Public Behavior Involving
  Children IS Exempt
• Participant Observation of Public Behavior
  Involving Children IS NOT Exempt
• IRB Needs Copy of All Surveys and Interview
  Scripts (unless standard test known to IRB)

73
Six Exemptions45 CFR 46.101(b)

• 3) Research involving the use of
• Educational tests (cognitive, diagnostic,
  aptitude, achievement), survey procedures,
  interview procedures, or observation of public
  behavior
• WHERE
• subjects are elected or appointed public
  officials or candidates for public office
• or
• Federal statutes require confidentiality without
  exception

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Six Exemptions45 CFR 46.101(b)

• 4) Research involving the collection or study of
• existing data, documents, records, specimens, if
• the sources are publicly available
• or
• the information is recorded by the investigator
  in such a manner that subjects cannot be
  identified, directly or through identifiers
  linked to the subjects.
• NOTE Even brief recording of identifiers or
  codes disqualifies the exemption

75
Definition of Existing

• Existing means
• All data has been collected (i.e., on the shelf)
  prior to the research
• For a purpose other than the proposed research
• Includes data (or specimens) collected in
  research and non research activities.

76
Six Exemptions45 CFR 46.101(b)

• 5) Research and demonstration programs designed
  to study, evaluate, or examine (Federal) Public
  Benefit or Service Programs
• 6) Taste and food quality evaluation and consumer
  acceptance studies involving
• wholesome foods without additives
• additives, chemical, contaminants below safe
  levels determined by FDA, EPA, USDA

77
Informed Consent
78
Eight Required Elements45 CFR 46.116(a)

• Statement that study is research and information
  on purposes/duration/procedures/experimental
  procedures
• Reasonably foreseeable risks or discomforts
• Reasonably expected benefits
• Alternative procedures (including availability
  off-protocol where applicable)
• How confidentiality will be maintained
• Information on compensation for injuries (unless
  minimal risk)
• Contact Persons for info on research, injury,
  subjects rights
• Voluntary participation, no penalty or loss of
  benefits for refusal or withdrawal

79
Six Additional Elements

• Statement that there may be risks which are
  unforeseeable
• Under what circumstances investigator could
  terminate subjects participation
• Additional costs to subject
• Consequences of subjects withdrawal from research
• Statement that will be told of new findings
• Approximate number of subjects in study

80
Informed ConsentSpecial Issues

• There is no such thing as passive consent
• consent is required unless formally waived
• documentation is required unless formally waived
  
• There is no such thing as a secondary subject
• if an investigator obtains identifiable private
  information about a living individual, the
  individual is a human subject, regardless of the
  source

81
Waiver of Informed Consent(Not Permitted Under
FDA Regulations)

• IRB must find and document that 4 criteria met
• Minimal risk research
• Waiver or alteration will not adversely affect
  the rights and welfare of the subjects
• Research could not practicably be carried out
  without the waiver or alteration
• Subjects will be provided with additional
  pertinent information

82
Documentation of Informed Consent

• Written consent document
• In language understandable to the subject or the
  subjects Legally Authorized Representative (LAR)
• Verification of translated consent document
• Signed by subject or subjects LAR
• Copy SHALL be given to subject
• Opportunity to read before signing

83
Documentation of Informed Consent

• Short form written consent document requires
• oral presentation
• witness to oral presentation
• an IRB approved written summary
• given to subject
• signed by witness
• signed by person obtaining consent
• short form documenting oral presentation
• signed by subject or LAR
• signed by witness

84
Waiver of Documentation of Informed Consent (Not
Permitted by FDA Regs)

• The Signed Consent Document provides the only
  link to the subjects identity and principal risk
  is breach of confidentiality
• The research presents no greater than minimal
  risk of harm to subjects and involves no
  procedures requiring consent in a non-research
  context
• IRB may require a subject information sheet

85
After IRB Approval
86
Adverse Events v. UPIRSO

• FDA Regulatory Terms
• Adverse Events
• Unanticipated Problems Involving Risks to
  Subjects and Others
• Reportable events

• HHS Regulatory Language
• Unanticipated Problems Involving Risks to
  Subjects and Others
• Reportable Events

87
Risks to Subjects

• Adverse events vs. unanticipated problems
• A risk or problem is unanticipated if it is not
  in the protocol or consent document.
• Risks discussed in the protocol should be
  included in the consent document
• Questions raised as a result of an unanticipated
  risk
• Does the informed consent form need to be
  amended?
• Do previously enrolled subjects need to be
  re-consented?
• Does a report need to be made to any government
  office?

88
Risks to Subjects

• If a risk is listed as rare in a protocol, and it
  becomes frequent, then it may be an unanticipated
  problem that has to be reported to OHRP.

89
Protocol Deviations

• Very detailed protocol
• Missing a dose
• Intervention on the wrong day
• All become protocol deviations

• Write protocols more broadly
• Range for dosing
• Ranging for timing
• Less likely that differences in regimen will
  become a protocol deviation

90
Protocol Deviations

• University of Oklahoma July 2000 suspension of
  research
• Testing of a vaccine on subjects with melanoma
• Three year trial
• Numerous violations of study protocol
• shipping vaccine to subjects for self-injection
• inadequate staffing
• inadequate supervision of sponsors manufacturing
  facilities

91
Protocol DeviationsUniv. of Oklahoma

• June 29, 2000 letter from OHRP to Univ. OK
• OHRP finds that the principal investigator
  implemented substantive changes to the research
  project without IRB approval. The changes made
  without IRB approval included, but are not
  limited to the following
• (a) The investigator deviated from the
  IRB-approved inclusion and exclusion criteria. In
  specific, 11 of the first 18 subjects enrolled in
  the protocol did not satisfy all IRB-approved
  inclusion/exclusion criteria. Of note, the IRB
  Chair unilaterally approved these deviations
  retroactively

92
Protocol DeviationsUniv. of Oklahoma (cont.)

• (b) Sample size was increased above the total
  subject number approved by the IRB (15 for phase
  I and 25 for phase II) by November 17, 1999,
  total subject enrollment had increased to more
  than 90.
• (c) The study vaccine was shipped to some
  subjects homes for self-administration by the
  subjects. Of note, the IRB-approved protocol
  prior to November 19, 1999 stated the following
• the Nurse Coordinator will give all injections.
  She will record any transient erythematous
  reactions and refer patients with any other side
  effects to Dr. McGee Patients will be required
  to remain in the physicians office for 30
  minutes afterward.

93
Protocol DeviationsUniv. of Oklahoma (cont.)

• (d) Some subjects were allowed to self-monitor
  for adverse local reactions following vaccine
  administration.
• (e) The investigator added several remote study
  sites and co-investigators.
• (f) Non-physicians were used to perform some
  protocol-stipulated physical exams that were to
  have been performed by a physician under the
  IRB-approved protocol.

94
FDA Issues
95
FDA Regulations

• Informed Consent - 21 CFR Part 50
• IRB Review - 21 CFR Part 56
• Investigational Drugs - 21 CFR Part 312
• Marketing Approval - 21 CFR Part 314
• Biologics - 21 CFR Part 600
• Biologics Licensing 21 CFR Part 601
• Investigational Devices - 21 CFR Part 812
• Pre-Market Approval 21 CFR Part 814
• Financial Disclosure 21 CFR Part 54
• Electronic Records 21 CFR Part 11

96
FDA Regulations

• Informed Consent -- 21 CFR 50
• Eight Required Elements
• Written Documentation
• Language Understandable to Subjects
• No Coercion or Undue Influence
• No Waiver of Subjects Rights
• IRB Review -- 21 CFR 56
• Initial Review
• Prospective Review of All Changes
• Reporting/Review of Unanticipated Problems
• Reporting/Review of Adverse Events
• Continuing Review at Least Annually

97
FDA Regulations

• Drugs and Biologics
• Investigational New Drug Application (IND)
• 21 CFR Part 312
• Devices
• Investigational Device Exemption (IDE)
• 21 CFR Part 812

98
FDA RegulationsWhen is an IND Needed?

• Any use in which a marketed or un-marketed drug
  is administered or dispensed to, or used
  involving, one or more human subjects, except
  for
• Use of a marketed drug in course of medical
  practice, or
• Investigation of a marketed drug where there is
• No intent to support a new indication for use or
  other significant change in labeling
• No intent to support a significant change in
  advertising
• No factor such as route of administration,
  dosage, or patient population that increases or
  decreases the acceptability of risks associated
  with the product
• Compliance with FDA Informed Consent and IRB
  Review requirements and
• No promotion or representation of the drug as
  safe or effective for the purpose under
  investigation.

99
FDA RegulationsResponsibilities of Sponsors

• Maintaining the IND
• Obtaining Qualified Investigators and Monitors
• Providing Necessary Information/Training for
  Investigators
• Monitoring the Investigation
• Controlling the Investigational Agent
• Reporting Significant Adverse Events to
  FDA/Investigators
• Maintaining and Retaining Accurate Records

100
FDA RegulationsResponsibilities of Investigators

• Specific Responsibilities
• Ensuring Conduct of the Research per the
  Investigator Agreement, Investigational Plan, and
  All Applicable Regulations
• Protecting the Rights, Safety, and Welfare of the
  Research Subjects
• Controlling access to and use of the test article
  (drug / biologic / device)
• Monitoring and Reporting Adverse Events
• Maintaining and Retaining Accurate Records

101
FDA Reporting RequirementsIND - Adverse Event
Reporting

• Investigator must report promptly (immediately if
  alarming) to the Sponsor any adverse effect that
  may reasonably be regarded as caused by the drug
  (21 CFR 312.64)
• Sponsor must notify FDA of any adverse experience
  associated with the drug that is both serious and
  unexpected
• Serious Adverse Drug Experience death,
  life-threatening, hospitalization, persistent
  /significant disability / incapacity, congenital
  anomaly / birth defect (21 CFR 312.32)
• Unexpected Drug Experience any adverse drug
  experience, the specificity or severity of which
  is not consistent with the current investigator
  brochure or IND application (21 CFR 312.32)

102
FDA Reporting RequirementsIDE - Adverse Event
Reporting

• Investigator must report any unanticipated
  adverse device effect to Sponsor and the IRB as
  soon as possible and within 10 working days 21
  CFR 812.150
• Sponsor must report any unanticipated adverse
  device effect to FDA, all reviewing IRBs, and
  investigators 21 CFR 812.150
• Unanticipated Adverse Device Effect any serious
  adverse effect on health or safety, or any
  life-threatening problem or death, caused by or
  associated with a device if not previously
  identified in nature, severity, or degree of
  incidence in the investigational plan or
  application 21 CFR 812.3

103
FDA Regulation Exceptions ExemptionsEmergency
Use of a Test Article

• Without Informed Consent 21 CFR 50.23(a)
• Life Threatening Situation Necessitating the Use
• Inability to Communicate with Subject for Legal
  Consent
• Insufficient Time to Obtain Consent from Legally
  Authorized Representative (LAR)
• No Alternative Therapy Available
• Certification in Writing from Investigator and an
  other Nonparticipating Physician of the Above
• Report to IRB Within 5 Working Days

104
FDA Regulation Exceptions ExemptionsEmergency
Use of a Test Article (cont.)

• No IRB Review 21 CFR 56.104 (c)
• Life Threatening Situation Necessitating the Use
• No Alternative Available
• Insufficient time for IRB review
• Report to IRB Within 5 Working Days
• Subsequent Use Requires IRB Review

105
FDA Regulations Single Patient IND

• Commonly referred to as compassionate use
• Requires Informed Consent and IRB review 21 CFR
  312.34
• See OHRS website for guidance

106
FDA Device Regulations Compassionate Use

• Compassionate Use of an Unapproved Device may be
  approved by FDA when it is the only option for a
  patient with a serious condition
• Requires as many of the following as possible
• Informed Consent
• Institutional Approval
• Concurrence of IRB Chair (but NOT IRB APPROVAL)
• Independent Assessment of Uninvolved Physician
• Authorization of the Sponsor

107
FDA Regulations DevicesSR Devices vs. NSR
Devices

• IRB Must Make a Specific Determination
• Significant Risk Device Investigational device
  that presents a potential for serious risk to the
  health, safety, or welfare of subjects, including
  implants
• Non-Significant Risk Device Investigational
  devices that does NOT present the potential for
  serious risk to the health, safety, or welfare of
  subjects
• Non-Significant Risk is NOT the same as Minimal
  Risk
• Once IRB-approves the research as not involving a
  Significant Risk Device, the research is
  considered to have an approved IDE, unless the
  FDA has notified the sponsor otherwise.

108
FDA Regulations Off-Label Use

• FDA-approved products (i.e., marketed products)
  may be used by physicians outside of labeled
  indications FOR THE PRACTICE OF MEDICINE
• Such use in RESEARCH (i.e., as part of a
  systematic investigation designed to develop or
  contribute to generalizable knowledge) requires
  IRB REVIEW
• Such use intended to support a CHANGE in labeling
  requires IRB REVIEW and an IND / IDE

109
FDA Regulations Standard of Care Comparisons

• Systematic comparison of FDA-approved products
  (i.e., marketed products) used for approved
  indications constitutes research and requires IRB
  review
• Systematic comparison of competing standards of
  care constitutes research and requires IRB review

110
FDA Regulations Humanitarian Device Exemption
(HDE)

• Humanitarian Use Device (HUD)
• Device tested but not profitable for marketing
• Requires
• IRB Review (Limited) and Approval
• No Research Informed Consent

111
FDA Regulations Planned Emergency Research

• Ordinarily Requires IRB Review and Informed
  Consent of Subject or Subjects Legally
  Authorized Representative (as determined by State
  Law for Research Contexts)
• Exception from Informed Consent Requirement
  Involves Many Specific IRB Determinations and
  Approval by FDA or OHRP

112
Protections for Vulnerable Subjects

• Under Sections 46.111
• Vulnerable to Coercion or Undue Influence
• eg Handicapped, Disabled, Economically or
  Socially Disadvantaged Persons
• HHS Subpart B
• Pregnant Women, Human Fetuses, and Neonates
• HHS Subpart C
• Prisoners
• HHS Subpart D
• Children

113
HHS Subpart B Research Involving Pregnant
Women, Human Fetuses, and Neonates

• Subpart B -- Revised December 2001
• Research involving pregnant women
• Research involving fetuses
• Research involving neonates of uncertain
  viability, nonviable neonates, or viable neonates

114
HHS Subpart B 45 CFR 46.204Research Involving
Pregnant Women or Fetuses

• Any research that TARGETS pregnant women or
  fetuses requires a special and specific
  regulatory review.
• Any such research should be submitted directly to
  senior staff at OPRS since the IRB will need
  special training for the review and approval of
  this type of research.

115
HHS Subpart C 45 CFR 46.303(c)Research
Involving Prisoners

• Definition of a Prisoner
• Any individual involuntarily confined or detained
  in a penal institution under a criminal or civil
  statute
• Individuals detained in other facilities as an
  alternative to criminal prosecution or
  incarceration in a penal institution
• Individuals detained pending arraignment, trial,
  or sentencing

116
HHS Subpart CResearch Involving Prisoners

• Subpart C
• Prisoner representative on OHRP approved roster
• Additional duties under 46.305
• Finding of permissible category under 46.306
• Certification to OHRP
• Concurrence from OHRP

117
Additional IRB DutiesHHS Subpart C 45 CFR 46.305

• Research is permissible within a 46.306 category
• Advantages of participating are not coercive
  given the limited choice prison environment
• Risks commensurate with those accepted by
  nonprisoner volunteers
• Selection procedures are fair
• Language is understandable to the subject
  population
• Participation has no affect on parole, and
  prisoners are so informed
• Adequate provisions will be made if there may be
  a need for follow-up care, and given varying
  lengths of sentences, and prisoners are so
  informed
• If HHS-supported, institution (IRB) certifies to
  OHRP that it has carried out its duties under
  these sections

118
Categories of Permissible Research HHS Subpart
C 45 CFR 46.306(b)

• The study of the possible causes, effects, and
  processes of incarceration, and of criminal
  behavior, provided that the study presents no
  more than minimal risk and no more than
  inconvenience to the subjects.

• The study of prisons as institutional structures
  or of prisoners as incarcerated persons, provided
  that the study presents no more than minimal risk
  and no more than inconvenience to the subjects.

119
Categories of Permissible Research HHS Subpart
C 45 CFR 46.306(b)

• Research on conditions particularly affecting
  prisoners as a class - ONLY AFTER DHHS
  CONSULTATION WITH EXPERTS AND PUBLICATION OF A
  NOTICE TO APPROVE IN THE FEDERAL REGISTER.

• Research on practices, both innovative and
  accepted, which have the intent and reasonable
  probability of involving the health or well-being
  of the subject. IF CONTROL GROUP WITH NO BENEFIT,
  CONSULTATION WITH EXPERTS AND FEDERAL REGISTER IS
  NOTICE REQUIRED.

120
Lawsuit Involving Prisoners

• DOJ funded research in Pennsylvania prison
• mandatory drug testing (urine vs. hair)
• no consent
• solitary confinement for refusal to be tested
• facts of case not contested
• Acres of Skin
• Dow, U Pennsylvania, City of Philadelphia
• Prisoners told experiments were harmless

121
Research involving Children
122
Definition of Minimal Risk

• Definition impacts
• Pediatric Studies
• Important for determining whether a research
  protocol or change in research can be expedited
  or must go to the full board.
• Waiver of Consent
• Document of Consent

123
Definition of Minimal RiskFDA, HHS, Federal
Policy

• Minimal Risk means
• The probability and magnitude of harm or
  discomfort
• Are not greater than those ordinarily encountered
  in daily life
• or
• During the performance of routine physical or
  psychological examinations or tests.

124
HHS Subpart D FDA Subpart DResearch Involving
Children

• Category Determinations Required
• Specific Approval Criteria for Each Category
• Protocol-Specific Justification Required
• Not greater than minimal risk
• Greater than minimal risk
• Prospect of direct benefit
• Greater than minimal risk
• No prospect of direct benefit
• Research not otherwise approvable

125
Subpart D 45 CFR 46.404 21 CFR 50.51 Research
involving no greater than minimal risk

• Children may be involved in research where the
  IRB finds that
• The research presents no greater than minimal
  risk to the child
• Adequate provision are made for obtaining
• The assent of the child
• The permission of the childs parents or guardians

126
NICHD Trial

• In the minutes of the NICHD IRB, they noted that
  for one protocol, there was more risk to children
  in crossing the street than in spending two days
  in the hospital hooked up to an IV line.

127
Subpart D 45 CFR 46.405 21 CFR 50.52Greater
than minimal risk but presenting prospect of
direct benefit to individual subjects

• Children may be involved in research where the
  IRB finds that more than minimal risk to children
  is presented by (i) an intervention or procedure
  that holds out the prospect of direct benefit for
  the individual subject, or (ii) a monitoring
  procedure that is likely to contribute to the
  subjects well-being if
• The risk is justified by anticipated benefit to
  subjects
• The relation of anticipated benefit to risk is at
  least as favorable as available alternatives
• Assent of child and permission of parents are
  sought.

128
Subpart D 45 CFR 46.406 21 CFR 50.53
Research involving greater than minimal risk and
no prospect of direct benefit to individual
subjects

• Children may be involved in research presenting
  more than minimal risk without the prospect of
  direct benefit or increased well being for the
  subject if
• Risk is a minor increase over minimal risk
• Research presents situations reasonably equal to
  to those inherent in their actual situations
• Research is likely to yield generalizable
  knowledge about disorder or condition
• Adequate provisions for obtaining child assent
  and parental permission.

129
Fenfluramine Study

• New York State Psychiatric Institute
• Mount Sinai School of Medicine
• Queens College
• The study focused on 34 boys between the ages of
  6 and 10 who had brothers with violent tendencies
  as reflected in court cases.
• The boys were given fenfluramine.
• Did children with siblings who were juvenile
  delinquents have a greater propensity towards
  juvenile delinquency.

130
Fenfluramine Study

• Since the study did not provide any benefit, was
  it likely to yield generalizable knowledge about
  an underlying condition or disorder?

131
Subpart D 45 CFR 46.407 21 CFR 50.54
Research not otherwise approvable but presenting
opportunity to understand, prevent, or alleviate
a serious problem affecting health or welfare of
children

• IRB finds the research presents opportunity as
  above
• HHS Secretary, after consultation with panel of
  experts public review and comment, determines
• The research presents reasonable opportunity as
  above
• The research will be conducted in accordance with
  sound ethical principles
• Adequate provisions are made for obtaining child
  assent and parental permission

132
Subpart D Research Involving ChildrenParental
Permission Required

• Permission of Both Parents Required If Greater
  than Minimal Risk, unless
• One parent not reasonably available
• One parent has sole custody
• Standard HHS Waiver Not Contained in FDA
  Regulations
• HHS Waiver in Interest of Child Not Contained in
  FDA Regulations
• 45 CFR 46.408

133
Subpart D Research Involving Children Assent
of Child Required

• Developmentally Appropriate as Determined by IRB
• Documentation as Determined by IRB
• Unless the Research Holds the Prospect of Direct
  Benefit Available Only in the Research
• Or
• Unless Waived by IRB per criteria at 45 CFR
  46.116(d)
• 45 CFR 46.408

134
What happens if a child reaches the legal age of
consent?

• Subject is a child enrolled in research
• Subject reaches the age of majority
• IRB can
• waive informed consent if can meet 4 regulatory
  requirements
• otherwise, investigators have to re-consent the
  individuals

135
Conflicts of Interest
136
Types of Conflict of Interest

• Individual
• Clinical investigators
• Study coordinators
• Research technicians
• Research officials
• IRB members
• Institutional
• Financial holdings of the institution
• Decisions regarding research funding or
  allocation of resources for research

• Financial
• Consulting fees
• Stock ownership
• Honoraria
• Salary
• Intellectual property rights
• Enrollment bonuses
• Spouse / dependent finances
• Professional
• Pressure to publish
• Professional rivalries
• Career advancement

137
Questions?